The combination of 5FU and leucovorin (LV) has resulted in significant increases in response rates and modest improvements in survival for patients with metastatic colorectal cancer. However, many patients are resistant to treatment at presentation and others acquire resistance during therapy. Resistance may be the result of provision of thymidylate via the alternate salvage pathway from intracellular or extracellular breakdown products of DNA. Persantine inhibits nucleoside transport at the cell membrane thereby blocking salvage of preformed nucleosides. Thus, extracellular nucleosides will be unable to enter the cell while lipid-soluble AZT can diffuse into the cell and compete with any thymidine generated by escape of TS inhibition by 5FU and LV or the intracellular salvage of nucleosides. The combination of these agents should lead to effective thymidine starvation and cell death. A phase I study using fixed doses of 5FU, LV and persantine with increasing doses of AZT (50 mg, 100 mg and 200 mg) has been completed. Dose-limiting toxicity was not observed and an AZT dose of 200 mg was chosen for the phase II study. The melanoma (14 patients) and renal cell (14 patients) portions of the phase II study have been completed and eight of a planned nine patients have been accrued to the colon cancer portion. Major toxicity was hematologic, with 13 episodes of grade III and 22 episodes of grade IV granulocytopenia. There were five episodes of greater than or equal to grade III thrombocytopenia and nine episodes of greater than or equal to grade III anemia. In renal cell carcinoma and metastatic melanoma, there have been zero complete or partial and three minor responses. In colon cancer, there has been one partial response in seven evaluable patients, with one patient too early to evaluate.